Author: Michelle Dryden

• DESTINY-Lung02 phase 2 trial shows clinically meaningful efficacy and favorable safety at 5.4 mg/kg dose versus 6.4 mg/kg dose of Daiichi Sankyo and AstraZeneca’s ENHERTU in HER2 mutant disease
• Updated results from DESTINY-Lung01 phase 2 trial demonstrate continued durable activity across patient subtypes

TOKYO & BASKING RIDGE, N.J. — (BUSINESS WIRE) — Detailed positive results from an interim analysis of the DESTINY-Lung02 phase 2 trial showed ENHERTU^® (trastuzumab deruxtecan) demonstrated clinically meaningful tumor responses in previously treated patients with HER2 mutant unresectable and/or metastatic non-squamous non-small cell lung cancer (NSCLC). Results will be presented today as a late breaking presentation (LBA55) at the European Society for Medical Oncology (#ESMO22) 2022 Congress.

ENHERTU is a specifically engineered HER2 directed antibody drug conjugate (ADC) being jointly developed and commercialized by Daiichi Sankyo (TSE:4568) and AstraZeneca (LSE/STO/Nasdaq: AZN).

At a pre-specified interim analysis of DESTINY-Lung02, with a data cutoff of March 24, 2022, patients receiving ENHERTU at a dose of 5.4 mg/kg (n=52) or 6.4 mg/kg (n=28) demonstrated clinically meaningful activity. The safety profile for both doses also was consistent with the overall safety profile of ENHERTU with the 5.4 mg/kg dose demonstrating a favorable safety profile in this patient population. A confirmed objective response rate (ORR) of 53.8% (95% confidence interval [CI], 39.5-67.8) and 42.9% (95% CI, 24.5-62.8) was seen in the 5.4 mg/kg and 6.4 mg/kg arms, respectively, as assessed by blinded independent central review (BICR). One complete response (CR) was observed in each arm (5.4 mg/kg: 1.9%, 6.4 mg/kg: 3.6%) with 27 (51.9%) partial responses (PR) observed in the 5.4 mg/kg arm and 11 (39.3%) PRs observed in the 6.4 mg/kg arm. At the pre-specified interim analysis, a median duration of response (DoR) was not reached in the 5.4 mg/kg arm and a median DoR of 5.9 months (95% CI: 2.8-NE) was seen in the 6.4 mg/kg arm. As median DoR was not reached in the 5.4 mg/kg arm, an additional 90-day follow-up response analysis was conducted, with a data cutoff of June 22, 2022, where ENHERTU demonstrated a confirmed ORR of 57.7% (95% CI, 43.2-71.3) and a median DoR of 8.7 months (95% CI: 7.1-NE) with CRs seen in 1.9% of patients and PRs in 55.8% of patients.

“DESTINY-Lung02 reinforces HER2 as an actionable mutation in patients with metastatic non-small cell lung cancer and further demonstrates that ENHERTU provides a clinically meaningful tumor response for these patients who have historically had limited treatment options,” said Koichi Goto, MD, Medical Oncologist and Investigator at National Cancer Center Hospital East, Kashiwa, Japan. “The response seen in this trial along with the disease control observed support ENHERTU as a potential treatment option in this type of non-small cell lung cancer.”

In DESTINY-Lung02, a favorable safety profile was observed in patients treated with ENHERTU 5.4 mg/kg with no new safety signals identified at either dose. Grade 3 treatment-emergent adverse events (TEAEs) were higher with ENHERTU 6.4 mg/kg versus 5.4 mg/kg (n=151). Grade 3 or higher treatment-related TEAEs occurred in 31.7% and 58.0% of all patients receiving ENHERTU 5.4 mg/kg or 6.4 mg/kg, respectively. The most common grade 3 or higher treatment-related TEAEs occurring in >10% of patients were neutropenia (11.9% (5.4 mg/kg), 34.0% (6.4 mg/kg)), anemia (8.9% (5.4 mg/kg), 14.0% (6.4 mg/kg)) and leukopenia (2.0% (5.4 mg/kg), 14.0% (6.4 mg/kg)). There were 13 cases (5.9% in the 5.4 mg/kg arm and 14% in the 6.4 mg/kg arm) of treatment-related ILD or pneumonitis reported as determined by an independent adjudication committee. The majority (5.4 mg/kg: 5.0%, 6.4 mg/kg: 14.0%) were low grade (grade 1 or 2), with one grade 3 event (5.4 mg/kg: 1.0%) reported. No grade 4 or grade 5 ILD or pneumonitis events occurred.

“The DESTINY-Lung02 results are consistent with the data previously seen with ENHERTU in non-small cell lung cancer and the efficacy demonstrated in this interim analysis, which supported the recent U.S. FDA accelerated approval of ENHERTU in patients with HER2 mutant non-small cell lung cancer, reinforces the potential to establish this medicine as a treatment option for these patients,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “These data will help inform future regulatory submissions worldwide with the goal of continuing to offer this innovative medicine to as many patients as possible.”

“The clinically meaningful activity, together with the favorable safety profile seen in the DESTINY-Lung02 trial helps establish the optimal dose of ENHERTU at 5.4 milligrams per kilogram in previously treated HER2 mutant non-small cell lung cancer,” said Cristian Massacesi, MD, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca. “As we continue to explore the potential of this important medicine across multiple HER2 targetable tumor types, these data reaffirm the need to undertake HER2 testing in patients diagnosed with lung cancer.”

All patients in DESTINY-Lung02 received at least one prior cancer therapy, including platinum-based chemotherapy. In the pre-specified early cohort, 71.2% and 78.6% of patients received prior anti-PD-1 therapy in the 5.4 mg/kg and 6.4 mg/kg arms, respectively. Median follow-up was 5.6 months (1.1-11.7) in the 5.4 mg/kg arm and 5.4 months (0.6-12.1) in the 6.4 mg/kg arm.

Summary of DESTINY-Lung02 Results

DESTINY-Lung01 Updated Results

Updated results from the DESTINY-Lung01 phase 2 trial, which evaluated ENHERTU in HER2 mutant (cohort 2) or HER2 overexpressing (cohort 1 and cohort 1a) NSCLC, also were presented at ESMO and showed that ENHERTU continues to demonstrate consistent efficacy, safety and survival with longer follow-up.

After a median follow-up of 16.7 months, results of previously-treated patients with HER2 mutant NSCLC (cohort 2) showed the median duration of response (DoR) for ENHERTU in the overall patient population increased to 10.6 months (95% CI: 5.6-18.3) with median overall survival (OS) increasing to 18.6 months (95% CI: 13.8-25.8). Subgroup analyses of patients with or without a presence of baseline asymptomatic brain metastases showed that treatment with ENHERTU resulted in a median PFS of 7.1 months (95% CI: 5.5-9.8) and 9.7 months (95% CI: 4.5-16.9), respectively and a median OS of 14.0 months (95% CI: 9.8-19.5) and 27.0 months (95% CI: 15.3-NE), respectively. The subgroup analysis of patients who had received either two or fewer prior therapies or more than two prior therapies showed a median PFS of 8.3 months (95% CI: 5.8-15.2) and 6.8 months (95% CI: 4.4-9.8), respectively and a median OS of 22.1 months (95% CI: 14.0-31.3) and 13.8 months (95% CI: 7.1-18.6), respectively.

Additionally, updated results from cohort 1 (ENHERTU 6.4 mg/kg; n=49) and cohort 1a (ENHERTU 5.4 mg/kg; n=41), which evaluated patients with previously-treated metastatic HER2 overexpressing NSCLC, highlight encouraging anti-tumor activity. At the data cutoff of December 3, 2021, in cohort 1, a confirmed ORR of 26.5% (95% CI: 15.0-41.1) was seen in patients receiving ENHERTU 6.4 mg/kg with a median PFS of 5.7 months (95% CI: 2.8-7.2) and a median OS of 12.4 months (95% CI: 7.8-17.2). In cohort 1a, a confirmed ORR of 34.1% (95% CI: 20.1-50.6) was seen in patients receiving ENHERTU 5.4 mg/kg, with a median PFS of 6.7 months (95% CI: 4.2-8.4) and a median OS of 11.2 months (95% CI: 8.4-NE). Median duration of follow-up was 12.0 months (95% CI: 0.4-36.0) and 10.6 months (95% CI: 0.6-16.9) in the 6.4 mg/kg and 5.4 mg/kg treatment groups, respectively.

The overall safety profile of ENHERTU in DESTINY-Lung01 was consistent with previous data, with no new safety signals identified with the longer follow-up. In the HER2 mutant NSCLC patient cohort, there was one additional case of treatment-related ILD or pneumonitis observed, as determined by an independent adjudication committee. ILD has been observed in 27.5% of patients treated with ENHERTU 6.4 mg/kg in the HER2 mutant cohort with the majority identified as low-grade and two grade 5 events occurring. In the HER2 overexpressing NSCLC patient cohorts, there were two additional cases of treatment-related ILD or pneumonitis observed in the 6.4 mg/kg dose arm and two cases observed in the 5.4 mg/kg dose cohort, as determined by an independent adjudication committee. ILD has been observed in 20.4% and 4.9% of patients treated with ENHERTU at the 6.4 mg/kg and 5.4 mg/kg doses, respectively, in the HER2 overexpressing cohort with the majority identified as low-grade and four grade 5 events occurring. Data from the DESTINY-Lung01 phase 2 trial were previously published in The New England Journal of Medicine.

ENHERTU is not approved outside the U.S. for the treatment of patients with metastatic HER2 mutant NSCLC.

About DESTINY-Lung02

DESTINY-Lung02 is a global, randomized phase 2 trial evaluating the safety and efficacy of ENHERTU in patients with HER2 mutant metastatic NSCLC with disease recurrence or progression during or after at least one regimen of prior anticancer therapy that must have contained a platinum-based chemotherapy. Patients were randomized 2:1 to receive ENHERTU 5.4 mg/kg (Cohort 1; n=102) or ENHERTU 6.4 mg/kg (Cohort 2; n=50). The primary endpoint of the study is confirmed ORR as assessed by BICR. Secondary endpoints include confirmed disease control rate (DCR), DoR and PFS assessed by investigator and BICR, investigator-assessed OS and safety. DESTINY-Lung02 enrolled 152 patients at multiple sites, including Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.

About DESTINY-Lung01

DESTINY-Lung01 is a global phase 2, open-label, two-cohort trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg or 6.4 mg/kg) in patients with HER2 mutant (cohort 2, n=91) or HER2 overexpressing (cohort 1 and 1a, n=90) (defined as IHC 3+ or IHC 2+) unresectable or metastatic non-squamous NSCLC who had progressed after one or more systemic therapies. The primary endpoint is confirmed ORR by independent central review (ICR). Key secondary endpoints include DoR, DCR, PFS, OS and safety. DESTINY-Lung01 enrolled 181 patients at multiple sites, including Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.

About HER2 Mutant and HER2 Overexpressing NSCLC

Lung cancer is the second most common form of cancer globally, with more than two million patients diagnosed in 2020.¹ For patients with metastatic NSCLC, prognosis is particularly poor, as only approximately 8% will live beyond five years after diagnosis.²

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors, including lung, breast, gastric and colorectal cancers. Certain HER2 (ERBB2) gene alterations (called HER2 mutations) have been identified in patients with non-squamous NSCLC as a distinct molecular target, and occur in approximately 2 to 4% of patients with this type of lung cancer.^3,4 While HER2 gene mutations can occur in a range of patients, they are more commonly found in patients with NSCLC who are younger, female and have never smoked.⁵ HER2 gene mutations have been independently associated with cancer cell growth and poor prognosis, with an increased incidence of brain metastases.⁶

Although the role of anti-HER2 treatment is well established in breast and gastric cancers, there were no approved HER2 directed therapies in NSCLC prior to the accelerated U.S. FDA approval of ENHERTU in unresectable or metastatic HER2 mutant NSCLC.⁷ Next-generation sequencing has been utilized in the identification of HER2 (ERBB2) mutations.⁸

HER2 overexpression is associated with a specific HER2 gene alteration known as HER2 amplification and is often associated with aggressive disease and poorer prognosis.⁹ It has been reported in approximately 10% to 15% of patients with NSCLC, with an incidence as high as 30% in those with adenocarcinoma (a subtype of cancer that grows in the glands that line the insides of organs).^10,11,12,13

About ENHERTU

ENHERTU^® (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the U.S. only) is a HER2 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, ENHERTU is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca’s ADC scientific platform. ENHERTU consists of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

ENHERTU (5.4 mg/kg) is approved in more than 30 countries for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received a (or one or more) prior anti-HER2-based regimen, either in the metastatic setting or in the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within six months of completing therapy based on the results from the DESTINY-Breast03 trial. ENHERTU also is approved in several countries for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received two or more prior anti-HER2-based regimens based on the results from the DESTINY-Breast01 trial.

ENHERTU (5.4 mg/kg) is approved in the U.S. for the treatment of adult patients with unresectable or metastatic HER2 low (immunohistochemistry (IHC) 1+ or IHC 2+/in-situ hybridization (ISH)-) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial.

ENHERTU (5.4 mg/kg) is approved under accelerated approval in the U.S. for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 trial. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

ENHERTU (6.4 mg/kg) is approved in several countries for the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 trial.

ENHERTU is approved in the U.S. with Boxed WARNINGS for Interstitial Lung Disease and Embryo-Fetal Toxicity. For more information, please see the accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide.

About the ENHERTU Clinical Development Program

A comprehensive global development program is underway evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2 targetable cancers including breast, gastric, lung and colorectal cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

Regulatory applications for ENHERTU in breast and gastric cancer are currently under review in several countries based on the DESTINY-Breast01, DESTINY-Breast03, DESTINY-Breast04, DESTINY-Gastric01 and DESTINY-Gastric02 trials, respectively.

About the Daiichi Sankyo and AstraZeneca Collaboration

Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU in March 2019 and datopotamab deruxtecan (Dato-DXd) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights for each ADC. Daiichi Sankyo is responsible for the manufacturing and supply of ENHERTU and datopotamab deruxtecan.

U.S. Important Safety Information

Indications

ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with:

• Unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen either:

  – In the metastatic setting, or

  – In the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy

• Unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy

• Unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy

• This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

• Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen

Contraindications

None.

Warnings and Precautions

Interstitial Lung Disease / Pneumonitis

Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU. A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in ≤28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose one level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate systemic corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks.

Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg)

In patients with metastatic breast cancer and HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, ILD occurred in 12% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 1.0% of patients treated with ENHERTU. Median time to first onset was 5 months (range: 0.9 to 23).

Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range: 1.2 to 21).

Neutropenia

Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 10⁹/L), interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 10⁹/L), interrupt ENHERTU until resolved to Grade 2 or less, then reduce dose by one level. For febrile neutropenia (ANC <1.0 x 10⁹/L and temperature >38.3º C or a sustained temperature of ≥38º C for more than 1 hour), interrupt ENHERTU until resolved, then reduce dose by one level.

Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg)

In patients with metastatic breast cancer and HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 65% of patients. Sixteen percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 22 days (range: 2 to 664). Febrile neutropenia was reported in 1.1% of patients.

Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, a decrease in neutrophil count was reported in 72% of patients. Fifty-one percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 16 days (range: 4 to 187). Febrile neutropenia was reported in 4.8% of patients.

Left Ventricular Dysfunction

Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU. Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage LVEF decrease through treatment interruption. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with ENHERTU. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with ENHERTU and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU.

Contacts

Global:
Victoria Amari

Daiichi Sankyo, Inc.

vamari@dsi.com
+1 908 900 3010 (mobile)

Japan:
Masashi Kawase

Daiichi Sankyo Co., Ltd.

kawase.masashi.a2@daiichisankyo.co.jp
+81 3 6225 1126 (office)

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• Extended follow-up data from phase 1/2 trial of DS-7300 in patients with metastatic lung, prostate or esophageal cancer to be featured in Proffered Paper session at ESMO

TOKYO, BASKING RIDGE, N.J. & NASHVILLE, Tenn. — (BUSINESS WIRE) — Daiichi Sankyo (TSE: 4568) and Sarah Cannon Research Institute (SCRI) announced that extended follow-up data from a phase 1/2 trial of DS-7300, a specifically designed potential first-in-class B7-H3 directed DXd antibody drug conjugate (ADC), continues to show promising durable tumor response in patients with several types of heavily pretreated cancers including lung, prostate or esophageal cancer. These data were presented today in a Proffered Paper session (Abstract #453O) at the European Society of Medical Oncology (#ESMO22) Congress.

B7-H3 is overexpressed in a wide range of cancer types, including lung, prostate and esophageal, and its overexpression has been shown to correlate with poor prognosis in some cancers, making B7-H3 a promising therapeutic target.^1,2,3,4,5,6

A response rate of 32% (95% CI: 24-41) was observed with 38 responses (33 confirmed; 28%; 95% CI: 20-37) in 118 patients with various solid tumors including small cell lung cancer (SCLC), squamous non-small cell lung cancer (NSCLC), metastatic castration-resistant prostate cancer (CRPC), esophageal squamous cell carcinoma (ESCC), head and neck squamous cell carcinoma (HNSCC) or endometrial cancer receiving doses of DS-7300 ranging from 4.8 mg/kg to 16.0 mg/kg.

“These results represent important progress in the development of DS-7300, which is continuing to show promising durable efficacy in patients with several different types of advanced cancers, including lung, prostate or esophageal cancer,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “Based on these results, we are evaluating next steps for the clinical development of DS-7300 beyond the phase 2 trial recently initiated in patients with extensive-stage small cell lung cancer.”

Lung Cancer Subset Efficacy Analyses

In two subsets of patients with advanced lung cancer, response rates of 58% (95% CI: 33-80) and 40% (95% CI: 5-85) were observed in patients with SCLC (n=19) and squamous NSCLC (n=5), respectively. Eleven responses (10 confirmed; 53%; 95% CI: 29-76) were seen in patients with SCLC and two confirmed responses (40%; 95% CI: 5-85) were seen in patients with squamous NSCLC. Median duration of response (DOR) was 5.5 months (95% CI: 2.8-NR) in patients with SCLC and 4.3 months (95% CI: 3.1-NR) in patients with squamous NSCLC. Median follow-up was 4.9 months (95% CI: 3.3-8.8) in patients with SCLC and 1.7 months (95% CI: 0.3-5.2) in patients with squamous NSCLC.

“All lung cancer patients except for one with squamous non-small cell lung cancer experienced a reduction in tumor size with DS-7300, which is potentially promising for patients looking beyond standard chemotherapy and immunotherapy options,” said Melissa L. Johnson, MD, Director, Lung Cancer Research, Sarah Cannon Research Institute at Tennessee Oncology. “We are eager to confirm the encouraging efficacy and safety results in patients with small cell lung cancer in an ongoing phase 2 trial currently enrolling patients with extensive-stage disease.”

Prostate Subset Efficacy Analysis

A response rate of 33% (95% CI: 21-47) was observed in a subset of patients in the dose escalation and expansion cohorts with metastatic CRPC (n=54). Eighteen responses (15 confirmed; 28%; 95% CI: 17-42) were seen in patients with metastatic CRPC and median DOR was 4.4 months (95% CI: 2.7-NR). Median follow-up was 9.3 months (95% CI: 7.5-10.6). For metastatic CRPC, 46% of patients had baseline liver metastases of which 40% of patients had a response.

Esophageal Subset Efficacy Analysis

A response rate of 23% (95% CI: 8-45) was observed in a subset of patients in the dose escalation and expansion cohorts with ESCC (n=22). Five responses (four confirmed; 18%; 95% CI: 5-40) were seen in patients with ESCC and median DOR was 2.8 months (95% CI: 2.6-NR). Median follow-up was 7.7 months (95% CI: 3.3-10.9).

Overall Safety

The safety and tolerability of DS-7300 was consistent with that previously reported from the trial. The most common treatment emergent adverse events (TEAEs) reported in >10% of all patients (n=147) were nausea (63%), anemia (33%), infusion-related reaction (32%), decreased appetite (31%), fatigue (30%), vomiting (30%), diarrhea (16%), pyrexia (16%), constipation (14%), chills (13%) and dehydration (11%). Grade ≥ 3 TEAEs occurred in 66 patients (45%), the most common of which were anemia (19%), neutropenia (4%), nausea (3%), pneumonia (3%) and decreased neutrophil count (3%). Two grade 1 and four grade 2 treatment-related interstitial lung disease (ILD)/pneumonitis events were reported at the 12.0 mg/kg dose and one grade 5 ILD event previously reported at the 16.0 mg/kg dose, which was discontinued due to safety concerns. These ILD events were adjudicated as drug-related by an independent adjudication committee. Two ILD/pneumonitis events are currently pending adjudication. Treatment discontinuations due to TEAEs occurred in 8% of patients.

“Prostate and esophageal cancer are two types of cancer that remain difficult to treat in advanced stages, where many patients experience repeated disease recurrence,” said Toshihiko Doi, MD, PhD, Director of Exploratory Oncology Research, Director of Clinical Trial Center and Center of Promotion of Translational Research, and Chief of Department of Experimental Therapeutics, National Cancer Center Hospital East. “Targeting the B7-H3 protein in both prostate and esophageal cancer with DS-7300 may be an encouraging treatment strategy for these patients who have limited treatment options in the metastatic setting.”

Patients enrolled in both the dose escalation and dose expansion parts of the trial across the 4.8 mg/kg to 16.0 mg/kg doses of DS-7300 received a median of five prior lines of therapies (range, 0-14). As of the data cut-off on June 30, 2022, 35 patients (24%) were still being treated with DS-7300 including eight patients (40%) with SCLC, 17 patients (23%) with metastatic CRPC, four patients (15%) with ESCC and five patients (56%) with squamous NSCLC. The expansion cohort in patients with squamous NSCLC remains open for enrollment.

About the DS-7300 Phase 1/2 Trial

This first-in-human, open-label phase 1/2 trial is evaluating the safety, tolerability and preliminary activity of DS-7300 in adult patients with advanced/unresectable or metastatic solid tumors that are refractory or intolerable to standard treatment or for whom no standard treatment exists.

The phase 1 part of the trial (dose escalation) is assessing the safety and tolerability of increasing doses of DS-7300 to determine the maximum tolerated dose (MTD) or recommended dose for expansion (RDE). This portion of the trial enrolled 81 patients with advanced/unresectable or metastatic SCLC, squamous NSCLC, metastatic CRPC, ESCC, HNSCC, bladder cancer, sarcoma, endometrial cancer, melanoma or breast cancer.

The phase 2 part of the trial (dose expansion) is evaluating the safety, tolerability and preliminary activity of DS-7300 at the RDE of 12.0 mg/kg in patients with squamous NSCLC, metastatic CRPC or ESCC.

The dose escalation part of the trial is evaluating dose-limiting toxicity and safety. The dose expansion part of the trial is evaluating ORR, DOR, disease control rate, progression-free survival, overall survival and safety. Pharmacokinetic endpoints, exploratory biomarker and immunogenicity endpoints also will be assessed.

Patient enrollment into the squamous NSCLC cohort of the dose expansion part of the trial remains underway in Asia and North America. For more information, please visit ClinicalTrials.gov.

About B7-H3

B7-H3 is a transmembrane protein that belongs to the B7 family, which also includes PD-L1.⁶ B7-H3 is overexpressed in a wide range of cancer types, including lung, prostate and esophageal, and its overexpression has been shown to correlate with poor prognosis in some cancers, making B7-H3 a promising therapeutic target.^1,2,3,4,5,6 Currently, no B7-H3 directed medicines are approved for the treatment of any cancer.

About Lung, Prostate and Esophageal Cancer

Lung cancer is the second most common cancer and the leading cause of cancer-related mortality worldwide with more than 2.2 million new cases and 1.7 million deaths in 2020.⁷ The two main types of lung cancer include NSCLC, which represents more than 80 to 85% of all cases, and SCLC, which comprises about 15% of cases.⁸ NSCLC is further divided into three subtypes including squamous cell carcinoma, which represents about 25% of cases and originates in squamous cells that line the inside of the airways in the lungs.⁸ More than half of patients with lung cancer are diagnosed in the metastatic stage.⁹ The five-year survival rate is only 8% and 3% for patients diagnosed with advanced NSCLC and SCLC, respectively.^10,11

Prostate cancer is the second most frequent cancer and the fifth leading cause of cancer death among men with an estimated 1.4 million new cases and 375,000 deaths worldwide in 2020.⁷ The five-year survival rate is only 32.3% for patients with metastatic prostate cancer.^12,13

Esophageal cancer is the tenth most common cancer worldwide and the sixth leading cause of cancer mortality with an estimated 604,000 new cases and 544,000 deaths reported in 2020.⁷ The majority of patients with esophageal cancer are diagnosed at advanced stage where the five-year survival rate is only 5.7%.^{14, 15}

About DS-7300

DS-7300 is an investigational B7-H3 directed ADC and is one of five ADCs currently in clinical development in the oncology pipeline of Daiichi Sankyo. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, DS-7300 is comprised of a humanized anti-B7-H3 IgG1 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

In addition to the phase 1/2 trial in collaboration with Sarah Cannon Research Institute, DS-7300 also is being evaluated by Daiichi Sankyo in a phase 2 trial in patients with extensive-stage SCLC.

DS-7300 is an investigational medicine that has not been approved for any indication in any country. Safety and efficacy have not been established.

About Daiichi Sankyo

Daiichi Sankyo is dedicated to creating new modalities and innovative medicines by leveraging our world-class science and technology for our purpose “to contribute to the enrichment of quality of life around the world.” In addition to our current portfolio of medicines for cancer and cardiovascular disease, Daiichi Sankyo is primarily focused on developing novel therapies for people with cancer as well as other diseases with high unmet medical needs. With more than 100 years of scientific expertise and a presence in more than 20 countries, Daiichi Sankyo and its 16,000 employees around the world draw upon a rich legacy of innovation to realize our 2030 Vision to become an “Innovative Global Healthcare Company Contributing to the Sustainable Development of Society.” For more information, please visit: www.daiichisankyo.com.

About Sarah Cannon Research Institute

Sarah Cannon Research Institute is the research arm of HCA Healthcare’s Cancer Institute, Sarah Cannon. Focused on advancing therapies for patients, it is one of the world’s leading clinical research organizations conducting community-based clinical trials. A leader in drug development, Sarah Cannon has led more than 600 first-in-human clinical trials since its inception in 1993, and has been a clinical trial leader in the majority of approved cancer therapies for more than a decade. Additionally, Sarah Cannon offers management, regulatory, and other research support services for drug development and industry sponsors through its contract research organization (CRO), Sarah Cannon Development Innovations.

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References:

¹ Yamato M, et al. Mol Cancer Ther. 2022;21:635–46.

² Dong P, et al. Front Oncol. 2018;8:264.

³ Picarda E, et al. Clin Cancer Res. 2016;22(14):3425-3431.

⁴ Bendell JC, et al. J Clin Oncol. 2020;39(15 suppl 1). Abstract TPS3646.

⁵ Kontos F, et al. Clin Cancer Res. 2021;27(5):1227-1235.

⁶ Qiu M-j, et al. Front. Oncol. 2021;11:600238.

⁷ Sung H, et al. CA Cancer J Clin . 2021;71(3): 209-249

⁸ Schabath MB and Cote ML. Cancer Epidemiol Biomarkers Prev. 2019 Oct;28(10):1563-1579

⁹ Chen R, et al. J Hematol Oncol. 2020;13(1):58

¹⁰American Cancer Society. NSCLC Survival Rates (SEER Data). Updated March 2022

¹¹ SEER. Small Cell Carcinoma of the Lung and Bronchus SEER 5-Year Relative Survival Rates. 2012-2018. Accessed September 2022

¹² NCI Seer Cancer Stats Prostate Cancer
¹³ NCI Seer Cancer Stat Facts Prostate Cancer by Stage
¹⁴ Yang J et al. Front Oncol. 2020; 10: 1727

¹⁵ NCI Seer Cancer Stat Facts: Esophageal Cancer

Contacts

Media Contacts:
Global:
Sarah McGovern

Daiichi Sankyo, Inc.

smcgovern@dsi.com
+1 908 821 7376 (mobile)

Investor Relations Contact:
DaiichiSankyoIR@daiichisankyo.co.jp

Japan:
Masashi Kawase

Daiichi Sankyo Co., Ltd.

kawase.masashi.a2@daiichisankyo.co.jp
+81 3 6225 1126 (office)

Late-Breaking presentation of phase 2 results from a clinical trial of GX-188E in combination with KEYTRUDA^® (pembrolizumab) demonstrates anti-tumor benefit in heavily pre-treated, recurrent and advanced cervical cancer

SEOUL, South Korea — (BUSINESS WIRE) — Genexine (KOSDAQ: 095700), a publicly traded, clinical-stage Korean biopharmaceutical company committed to the discovery and development of novel biologics for the treatment of unmet medical needs, today announced that GX-188E, its first-in-class proprietary DNA vaccine, demonstrated potent efficacy and favorable safety in patients with advanced cervical cancer in a phase 2 study when given in combination with KEYTRUDA^® (pembrolizumab), MSD’s (Merck & Co., Inc., Rahway, NJ, USA) anti-PD-1 therapy.

A total of 60 patients with HPV 16- and/or 18- positive advanced cervical cancer were analyzed in the phase 2 treatment group. Top line results showed a Best Overall Response Rate (BORR) of 31.7% (19 of 60 patients). 6 patients (10.0%) had a complete response and 13 patients (21.7%) had a partial response. Median duration of response (DOR) was 12.3 months and overall survival (OS) was 17.2 months.

The BORR increased to 38.5% in PD-L1 positive patients with HPV 16+ and Squamous Cell Carcinoma. Importantly, PD-L1 negative patients showed an ORR of 25.0%, which is extremely encouraging for this patient population, as it demonstrates potential improvement in efficacy compared to monotherapy of immune checkpoint inhibitors, suggesting a beneficial effect of the combination therapy.

In the safety analysis (n=65) 22 of 65 patients (33.8%) had treatment-related adverse events (TRAEs) of any grade and three (4.6%) had grade 3 or 4 TRAEs. The combination therapy was found to be safe and tolerable with a similar safety profile to that of pembrolizumab monotherapy.

“There is an urgent need for better therapies for patients with advanced cervical cancer and the combination of a therapeutic DNA vaccine together with checkpoint inhibition could be a strong alternative,” said professor Sung-Jong Lee of the Catholic University of Korea, College of Medicine and Investigator in the trial. “The data are very encouraging and appear to show a clear efficacy signal and the product appears safe and well tolerated. I am particularly pleased to see a clear efficacy signal in all patients, regardless of PD-L1 expression. Genexine’s combination therapy has strong appeal from a mechanistic perspective. This approach of using checkpoint inhibition to restore immune system function combined with the vaccine’s effect of upregulating and increasing the influx of CD8+ and other immune cells into the tumor microenvironment, appears to result in a strong, beneficial effect as demonstrated by major outcome measures such as BORR (31.7%) and OS (17.2 months) through the elimination of tumor cells and tumors.”

“We are very pleased to have been invited to present our phase 2 top-line data at ESMO and encouraged by the efficacy and safety shown in this study,” said Neil Warma, President and CEO of Genexine. “The combination of GX-188E, our unique DNA vaccine, with pembrolizumab could represent a new standard of care for patients with HPV 16/18 related recurrent or metastatic cervical cancer, regardless of PD-L1 expression. We are encouraged by the ORR of over 31% but particularly excited by the efficacy signal observed in PD-L1 negative patients. This could open the door to a new therapy for this patient population that previously had limited treatment options available.”

The clinical trial was an open-label, single-arm, phase 2 trial conducted in South Korea in patients with HPV-16 or HPV-18 positive advanced cervical cancer, and who had progressed after standard-of-care therapy. Patients received intramuscular 2 mg GX-188E at weeks 1, 2, 4, 7, 13, 19, and optional dose at week 46, and intravenous pembrolizumab 200 mg every 3 weeks for up to 2 years or until disease progression. The primary endpoint was ORR assessed by the blinded independent central reviewers (BICR) using RECIST version 1.1.

KEYTRUDA^® is a registered trademark of Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ.

About Genexine

Genexine, Inc. is a publicly traded, clinical-stage biotechnology company focused on the development and commercialization of immunotherapeutics and next-generation long-acting biologics. Primary technology platforms are Therapeutic DNA vaccine technology and hyFc^® fusion technology. The company has multiple products in clinical development, including several undergoing phase 3 registration trials. The company’s proprietary pipeline includes GX-188E for cervical cancer and head and neck cancer, GX-I7 (efineptakin alfa) for multiple cancers, GX-H9 (eftansomatropin alfa) for Growth Hormone Deficiency and GX-E4 for CKD-induced anemia, among others. Genexine has established multiple partnerships with global companies in order to expedite product development and commercialization and create significant value. Genexine is listed on the Korean stock exchange (KOSDAQ: 095700) and is headquartered in Seoul, Korea. Genexine is committed to the well-being and care of patients worldwide.

About GX-188E

GX-188E is a novel DNA-based therapeutic vaccine discovered by Genexine and being jointly developed with the National Cancer Center Korea Onco-Innovation Unit (NOIU). It has a mechanism of inducing an antigen-specific T-cell immune response to E6/E7, a cancer-causing protein produced by HPV types 16 and 18, which are the main causes of cervical cancer. The T cells with activated immune response have an immune-anticancer mechanism that effectively eliminates cervical cancer cells by inducing a cytotoxic T lymphocyte response. Genexine is currently developing GX-188E in cervical cancer and is also conducting two on-going combination trials with GX-188E in Squamous Cell Carcinoma of the Head and Neck (SCCHN).

About Cervical Cancer

Cervical cancer is a cancer arising from the cervix and is due to the abnormal growth of cells that have the ability to invade or spread to other parts of the body. Human Papilloma Virus (HPV) causes more than 90% of cases and HPV 16 and 18 strains are responsible for the majority of high grade cervical cancers. According to WHO, cervical cancer is the fourth most common cancer among women globally, with an estimated 604,000 new cases and 342,000 deaths in 2020. A recent Arizton research report estimated that the cervical cancer therapeutics market was $5.5 billion in 2021 and expected to grow at a CAGR of 4.14% during 2021-2027 to reach $7.1 billion with targeted therapies expected to be the fastest-growing segment during the forecast period.

Forward Looking Statements

This press release contains forward-looking statements regarding the business of Genexine, Inc. (“Genexine”). Any statement describing Genexine’s goals, expectations, financial or other projections, intentions or beliefs, development plans and the commercial potential of Genexine’s drug development pipeline, including without limitation GX-I7 (efineptakin alfa), GX-188E, GX-H9 (eftansomatropin alfa), GX-E4 is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to risks and uncertainties, particularly those challenges inherent in the process of discovering, developing and commercialization of new drug products that are safe and effective for use as human therapeutics and in the endeavor of building a business around such drugs.

Genexine’s forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Genexine’s forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Genexine. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Genexine’s programs are described in additional detail in Genexine’s annual reports on DART (Data Analysis, Retrieval and Transfer System) internet site (https://dart.fss.or.kr/) of the Korean Financial Supervisory Service. Genexine assumes no obligation to update the forward-looking statements or to update the reasons why actual results could differ from those projected in the forward-looking statements, except as required by law.

Contacts

For further information, please contact Genexine Investor Relations:

Mr. Edward Shin

edward.shin@genexine.com

Mr. Jongsoo Lee

jongsoo.lee@genexine.com